Puget N, Stoppa-Lyonnet D, Sinilnikova O M, Pagès S, Lynch H T, Lenoir G M, Mazoyer S
International Agency for Research on Cancer, Lyon, France.
Cancer Res. 1999 Jan 15;59(2):455-61.
Most previous BRCA1 mutation screening studies conducted on breast cancer families were aimed at identifying mutations in the coding sequence and splice sites. Mutations in the promoter and untranslated regions, and large rearrangements are missed by standard mutation detection strategies. To look specifically for such germ-line mutations in the BRCA1 gene, we have analyzed a series of 27 American and 51 French breast cancer families in which no BRCA1 mutation was identified by classical techniques. No mutations were detected in either the promoter or untranslated regions, and we did not find any deletion of the whole gene. Four families were found to carry distinct deletions. Two of them, probably generated by Alu-mediated homologous recombination, were internal deletions of 3 and 23.8 kb, encompassing exon 15 and exons 8-13, respectively. These alterations both lead to a frameshift in the mutant mRNA and to premature stop codon-mediated mRNA decay. The other two deletions encompass exons 1 and 2. On the basis of previous and present analyses, rearrangements represent 8% (3/37) of all mutations in our set of BRCA1 American families. Consequently, the search for rearrangements appears mandatory in BRCA1 mutation screening studies.
以往大多数针对乳腺癌家族开展的BRCA1突变筛查研究旨在鉴定编码序列和剪接位点中的突变。启动子和非翻译区的突变以及大片段重排会被标准突变检测策略遗漏。为了专门寻找BRCA1基因中的此类种系突变，我们分析了一系列27个美国家族和51个法国家族，这些家族通过经典技术未鉴定出BRCA1突变。在启动子或非翻译区均未检测到突变，并且我们未发现整个基因的任何缺失。发现四个家族携带不同的缺失。其中两个可能由Alu介导的同源重组产生，分别是3 kb和23.8 kb的内部缺失，分别涵盖外显子15和外显子8 - 13。这些改变均导致突变mRNA发生移码，并导致过早的终止密码子介导的mRNA降解。另外两个缺失涵盖外显子1和2。根据之前和目前的分析，重排在我们这组BRCA1美国家族的所有突变中占8%（3/37）。因此，在BRCA1突变筛查研究中，寻找重排显得必不可少。
